ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.2389+1G>T

dbSNP: rs879255186
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237166 SCV000295970 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge RCV000237166 SCV000599412 pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter curation
Robarts Research Institute, Western University RCV000237166 SCV000782939 pathogenic Hypercholesterolemia, familial, 1 2018-01-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV002450746 SCV002737079 pathogenic Cardiovascular phenotype 2020-08-11 criteria provided, single submitter clinical testing The c.2389+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 16 of the LDLR gene. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the missing amino acids is unknown; however, the impacted region is critical for protein function (Ambry internal data; Holla ØL et al. Mol. Genet. Metab., 2009 Apr;96:245-52). This variant has been detected in multiple individuals who met diagnostic or clinical criteria for familial hypercholesterolemia (Lombardi MP et al. Clin. Genet., 2000 Feb;57:116-24; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8; van der Graaf A et al. Circulation, 2011 Mar;123:1167-73). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp RCV002518499 SCV003443883 pathogenic Familial hypercholesterolemia 2024-09-02 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 16 of the LDLR gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with LDLR-related conditions (PMID: 10735632, 32041611, 32977124; internal data). ClinVar contains an entry for this variant (Variation ID: 252300). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

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